The goals of the present proposal are to elucidate the molecular mechanisms involved in the interaction of FXI/FXIa with protein and cell surface ligands that are involved in its (XI) activation, and with the plasma protein and cell surface ligands that are involved in the expression and regulation of its (XIa) enzymatic activity. Specifically, the applicant proposes to further fine map: (1) the regions (A45-S86) in the Apple 1 (A1) domain of factor XI involved in its interaction with the cofactor HMWK; (2) the regions (A317-G350) in the apple 4 (A4) domain of factor XI involved in its interaction with the enzyme factor XIIa; (3) the regions (P229-R266) in the apple 3 (A3) domain of factor XI involved in its interaction with the platelet binding site, and (4) the regions (A134- L172) in the apple 2 (A2) domain of factor XI involved in its interaction with the substrate factor IX. Another goal of the application is to understand the structural and functional basis and the physiological relevance of FXI activation by thrombin.